Elizabeth N. Bess

Multidimensional steric parameters in the analysis of asymmetric catalytic reactions

Although asymmetric catalysis is universally dependent on spatial interactions to impart specific chirality on a given substrate, examination of steric effects in these catalytic systems remains empirical. Previous efforts by our group and others have seen correlation between steric parameters developed by Charton and simple substituents in both substrate and ligand; however, more complex substituents were not found to be correlative. Here, we review and compare the steric parameters common in quantitative structure activity relationships (QSAR), a common method for pharmaceutical function optimization, and how they might be applied in asymmetric catalysis, as the two fields are undeniably similar. We re-evaluate steric/enantioselection relationships, which we previously analysed with Charton steric parameters, using the more sophisticated Sterimol parameters developed by Verloop and co-workers in a QSAR context. Use of these Sterimol parameters led to strong correlations in numerous processes where Charton parameters had previously failed. Sterimol parameterization also allows for greater mechanistic insight into the key elements of asymmetric induction within these systems.

Interrogating selectivity in catalysis using molecular vibrations.

The delineation of molecular properties that underlie reactivity and selectivity is at the core of physical organic chemistry, and this knowledge can be used to inform the design of improved synthetic methods or identify new chemical transformations. For this reason, the mathematical representation of properties affecting reactivity and selectivity trends, that is, molecular parameters, is paramount. Correlations produced by equating these molecular parameters with experimental outcomes are often defined as free-energy relationships and can be used to evaluate the origin of selectivity and to generate new, experimentally testable hypotheses. The premise behind successful correlations of this type is that a systematically perturbed molecular property affects a transition-state interaction between the catalyst, substrate and any reaction components involved in the determination of selectivity. Classic physical organic molecular descriptors, such as Hammett, Taft or Charton parameters, seek to independently probe isolated electronic or steric effects. However, these parameters cannot address simultaneous, non-additive variations to more than one molecular property, which limits their utility. Here we report a parameter system based on the vibrational response of a molecule to infrared radiation that can be used to mathematically model and predict selectivity trends for reactions with interlinked steric and electronic effects at positions of interest. The disclosed parameter system is mechanistically derived and should find broad use in the study of chemical and biological systems.

Analyzing Site Selectivity in Rh2(esp)2-Catalyzed Intermolecular C–H Amination Reactions

Predicting site selectivity in C–H bond oxidation reactions involving heteroatom transfer is challenged by the small energetic differences between disparate bond types and the subtle interplay of steric and electronic effects that influence reactivity. Herein, the factors governing selective Rh2(esp)2-catalyzed C–H amination of isoamylbenzene derivatives are investigated, where modification to both the nitrogen source, a sulfamate ester, and substrate are shown to impact isomeric product ratios. Linear regression mathematical modeling is used to define a relationship that equates both IR stretching parameters and Hammett σ+ values to the differential free energy of benzylic versus tertiary C–H amination. This model has informed the development of a novel sulfamate ester, which affords the highest benzylic-to-tertiary site selectivity (9.5:1) observed for this system.

Quantitatively Analyzing Metathesis Catalyst Activity and Structural Features in Silica-Supported Tungsten Imido–Alkylidene Complexes

A broad series of fully characterized, well-defined silica-supported W metathesis catalysts with the general formula [(≡SiO)W(═NAr)(═CHCMe2R)(X)] (Ar = 2,6-iPr2C6H3 (AriPr), 2,6-Cl2C6H3 (ArCl), 2-CF3C6H4 (ArCF3), and C6F5 (ArF5); X = OC(CF3)3 (OtBuF9), OCMe(CF3)2 (OtBuF6), OtBu, OSi(OtBu)3, 2,5-dimethylpyrrolyl (Me2Pyr) and R = Me or Ph) was prepared by grafting bis-X substituted complexes [W(NAr)(═CHCMe2R)(X)2] on silica partially dehydroxylated at 700 °C (SiO2-(700)), and their activity was evaluated with the goal to obtain detailed structure-activity relationships. Quantitative influence of the ligand set on the activity (turnover frequency, TOF) in self-metathesis of cis-4-nonene was investigated using multivariate linear regression analysis tools. The TOF of these catalysts (activity) can be well predicted from simple steric and electronic parameters of the parent protonated ligands; it is described by the mutual contribution of the NBO charge of the nitrogen or the IR intensity of the symmetric N-H stretch of the ArNH2, corresponding to the imido ligand, together with the Sterimol B5 and pKa of HX, representing the X ligand. This quantitative and predictive structure-activity relationship analysis of well-defined heterogeneous catalysts shows that high activity is associated with the combination of X and NAr ligands of opposite electronic character and paves the way toward rational development of metathesis catalysts.

Designer substrate library for quantitative, predictive modeling of reaction performance

Significance Product distributions of chemical reactions are dictated by a myriad of interactions between molecular species. Identifying which of these features affects reaction selectivity is a key facet for mechanistically understanding a transformation. Such insight often facilitates optimization as well as indicates which types of substrates (substrate scope) are well suited to the method. Unfortunately, the assessment of impactful features is frequently a qualitative endeavor that would significantly benefit from quantitation. We demonstrate a robust method for developing a varied substrate scope library of ketones, identifying quantitative descriptors of mechanistic significance, and applying these descriptors to mathematically elucidate trends in enantioselective reaction outcomes of rhodium-catalyzed asymmetric transfer hydrogenation. The developed mathematical relationships were used to predict future outcomes of new ketone substrates. Assessment of reaction substrate scope is often a qualitative endeavor that provides general indications of substrate sensitivity to a measured reaction outcome. Unfortunately, this field standard typically falls short of enabling the quantitative prediction of new substrates’ performance. The disconnection between a reaction’s development and the quantitative prediction of new substrates’ behavior limits the applicative usefulness of many methodologies. Herein, we present a method by which substrate libraries can be systematically developed to enable quantitative modeling of reaction systems and the prediction of new reaction outcomes. Presented in the context of rhodium-catalyzed asymmetric transfer hydrogenation, these models quantify the molecular features that influence enantioselection and, in so doing, lend mechanistic insight to the modes of asymmetric induction.

Distinctive Meta-Directing Group Effect for Iridium-Catalyzed 1,1-Diarylalkene Enantioselective Hydrogenation

An iridium-catalyzed asymmetric hydrogenation of 1,1-diarylkenes is described. Employing a novel, modular phosphoramidite ligand, PhosPrOx, in this transformation affords biologically relevant 1,1-diarylmethine products in good enantiomeric ratios (96.5:3.5 to 71:29). We propose that a meta-directing group, 3,5-dimethoxyphenyl, is responsible for the observed enantioselection, the highest reported, to date, for iridium-catalyzed hydrogenation of 1,1-diarylalkenes lacking ortho-directing groups.

Using IR vibrations to quantitatively describe and predict site-selectivity in multivariate Rh-catalyzed C–H functionalization

Achieving selective C–H functionalization is a significant challenge that requires discrimination between many similar C–H bonds.

Treatment of Low-risk Pulmonary Embolism Patients in a Chest Pain Unit

BACKGROUND Several studies have proposed the Pulmonary Embolism Severity Index (PESI) as a risk stratification tool for discharge of low-risk pulmonary embolism (PE) patients from the emergency department (ED) and treatment as outpatients, but this has not become accepted standard of care in the United States. Chest pain units (CPUs) may serve as ideal locations for the treatment and risk-stratification of low-risk PE patients, thus avoiding lengthy inpatient stays while assuring patients are appropriate for outpatient therapy for PE. We sought to characterize the number of patients at our institution who may be eligible for a short stay in our CPU and then established a protocol for the treatment of low-risk patients in the CPU. METHODS We identified all patients admitted to the University of Utah Medical Center from the ED with a diagnosis of PE over the 6-year period between 2002 and 2007. We retrospectively reviewed the electronic medical records to identify clinical variables to calculate a PESI score for each patient. Patients who were considered to be low-risk, on the basis of PESI score (class I and II), were considered eligible for treatment in the CPU, and, on the basis of this, we estimated numbers of patients to be treated in the CPU and patient demographics. We determined results of transthoracic echocardiography (TTE) and bilateral lower extremity (BLE) venous duplex ultrasound for PE patients to estimate potential inpatient admission rates from the CPU. We reviewed the electronic medical records during the 30-day period after hospital admission for patient mortality. We then created a protocol for the treatment of these low-risk patients in the CPU. RESULTS A total of 545 patients were admitted with PE during the 6-year period. Of these patients, 282 were considered low risk and potentially appropriate for treatment of PE in the CPU. Of those, 43.3% were male, and the average age was 43.9 years (range: 14-92 years). Mortality was 0% for the low-risk group over the 30 days after hospital admission. A total of 108 patients had TTE performed and, of these, 30 had evidence of right heart strain. Ninety patients had BLE venous duplex and, of these, 15 had a deep venous thrombosis proximal to the popliteal veins. On the basis of our findings, we created a protocol for treatment of low-risk PE patients in the CPU. Patients who are low risk according to PESI score are admitted to the CPU with administration of low-molecular-weight heparin in the ED and initiation of oral anticoagulation therapy. Patients are monitored on telemetry for at least 12 hours, with performance of BLE duplex and TTE while in the CPU. Patients are admitted to an inpatient unit from the CPU if during their stay they exhibit unstable vital signs, a new arrhythmia, deep venous thrombosis proximal to the popliteal veins on BLE duplex, or signs of right heart strain on TTE. Patients who do not meet these criteria are considered appropriate for outpatient treatment and discharged with low-molecular-weight heparin and oral anticoagulation with thrombosis clinic follow-up. Given our findings from the retrospective chart review, we estimated that, at our institution, 4 patients per month would be eligible for treatment of PE in the CPU. With the findings on TTE and BLE duplex, we estimated that 25.3% of eligible patients would eventually require inpatient admission from the CPU. CONCLUSIONS We identified a number of low-risk patients who may be eligible for treatment of PE in our CPU. Given the resources of the CPU, this may serve as an ideal location for the treatment of low-risk PE patients and allow further risk stratification and consultation beyond that typically readily available in the ED. We described the creation of a protocol for the treatment of low-risk patients with PE in a CPU.

EDOU staffing by PAs: what are the effects on patient outcomes?

Objective: An emergency department observation unit (EDOU) opened in April 2006 staffed by physician assistants (PAs) and nurse practitioners (NPs). This study describes the complexity and outcomes of the EDOU patients to determine the effectiveness of staffing by PAs. Methods: A retrospective chart review was performed of chest pain and trauma patients in the EDOU from April 2006 through May 2007. Patient characteristics, length of stay (LOS), and admission rates were recorded. Adverse events were monitored, and trauma patients were followed for 30 days to evaluate for missed injuries. Results: 531 chest pain patients and 364 trauma patients were admitted to the EDOU during the study period. Average chest pain patient LOS was 14 hours and 32 minutes, and 12.2% of patients were admitted from the EDOU to an inpatient unit. For trauma patients, average LOS was 12 hours and 46 minutes, and 11.5% of patients were admitted to an inpatient unit. There were no deaths, intubations, or loss of vital signs. In 30‐day follow‐up, there were no significant missed injuries among trauma patients. Conclusion: PAs effectively cared for patients of moderate complexity in the two largest groups of utilizers of the EDOU.

The Genetic Basis for the Cooperative Bioactivation of Plant Lignans by a Human Gut Bacterial Consortium

Plant-derived lignans, consumed daily by most individuals, are inversely associated with breast cancer; however, their bioactivity is only exerted following gut bacterial conversion to enterolignans. Here, we dissect a four-species bacterial consortium sufficient for all four chemical reactions in this pathway. Comparative genomics and heterologous expression experiments identified the first enzyme in the pathway. Transcriptional profiling (RNAseq) independently identified the same gene and linked a single genomic locus to each of the remaining biotransformations. Remarkably, we detected the complete bacterial lignan metabolism pathway in the majority of human gut microbiomes. Together, these results are an important step towards a molecular genetic understanding of the gut bacterial bioactivation of lignans and other plant secondary metabolites to downstream metabolites relevant to human disease. One Sentence Summary Bess et al. provide a first step towards elucidating the molecular genetic basis for the cooperative gut bacterial bioactivation of plant lignans, consumed daily by most individuals, to phytoestrogenic enterolignans.